Mycobacteria have plagued humanity for several millennia by causing major diseases like tuberculosis (TB), leprosy and Buruli ulcer. In terms of disease burden and mortality, TB is incontestably the most important and challenging threat to human health, in part because of the increasing prevalence of primary resistance to the current drugs. There is thus a growing need for new compounds with a novel mode of action (Balganesh, T. S., P. M. Alzari, and S. T. Cole. Trends Pharmacol Sci, 2038. 29(11): p. 576-81.) and these may also find application in treating other mycobacterial diseases and infections due to other Corynebacterineae. Leprosy is nearing elimination as a public health problem (Britton, W. J. and D. N. Lockwood. Lancet, 2004, 363(9416): p. 1209-19), thanks to the control measures implemented by the World Health Organisation, while the emerging disease, Buruli ulcer, is of growing concern (Demangel, C., T. P. Stinear, and S. T. Cole. Nat Rev Microbiol, 2009. 7(1): p. 50-60).
In the past twenty years, drug-resistant tuberculosis has reached an alarming level. In the 1990s, there had been increasing concern about the multidrug-resistant (MDR) form, where Mycobacterium tuberculosis has acquired resistance to the main front-line drugs, i.e. isoniazid and rifampicin. There are an estimated 500,000 cases of MDR-TB worldwide of which ˜70,000 occur in Europe (Zignol, M. et al. J Infect Dis, 2006. 194: 479-485; Fears, R. S. Kaufmann, V. Ter Meulen & A. Zumla. Tuberculosis (Edinb) 2010. 90: 182-187).
In the past decade, MDR-strains of M. tuberculosis have acquired additional resistance mutations to second line drugs giving rise to extensively drug-resistant (XDR) disease. In addition to isoniazid and rifampicin, XDR strains of M. tuberculosis are also resistant to fluoroquinolones and to the injectable aminoglycosides (Jassal, M. & W. R. Bishai. Lancet Infect Dis 2009. 9: 19-30). Over 50 countries have now reported XDR-TB, thereby underlining the necessity and importance of finding new drugs to treat both drug-sensitive and drug-resistant TB. In addition to a new mechanism of action, a new TB drug advantageously exhibits high potency, so that treatment duration can be reduced; and high specificity, so that side-effects including destruction of the gut flora can be avoided. Preferably, the new drug is suitable for oral administration.
2-Amino substituted 1,3-benzothiazine-4-ones can be used as drugs for the treatment of mycobacterial diseases in humans and mammals. Presently, the most active compounds available are 2-[(2S)-2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothia-zin-4-one (BTZ043) (V. Makarov et al. Science, 2009, 324, 801; M. R. Pasca, et al. Antimicrob, Agents Chemother., 2010, 54, 1616) and 2-[4-(cyclohexylmethyl)piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one (PBTZ169) (V. Makarov et al. EMBO Mol Med. 2014, 6(3):372-83).
It is thus desirable to provide drugs effective in the treatment of mammalian infections caused by bacteria, especially disease such as tuberculosis, Buruli ulcer and leprosy with an improved inhibitory activity. Preferably, these drugs are effective against MDR- and XDR-strains as well as strains which are resistant against other drugs.
Recent methods for the synthesis of 2-amino substituted 1,3-benzothiazine-4-ones are described e.g. in WO 2007/134625, WO 2009/010163 and EP 2 029 533. These methods include:    1) Reacting 2-chlorobenzcarboxamide with a substituted piperazine sodium dithiocarbamate (e.g. WO 2009/010163, method A to C).
                This reaction results in the formation of free H2S, which can result in undesirable side products, thereby negatively influencing purity and yield.            2) Reacting 2-chlorobenzcarboxamide with a metal alkylxantogenate. The isolated 2-alkoxy-4H-1,3-benzothiazine-4-one is further reacted with a secondary amine (WO 2009/01063).
                The reaction is a two-step reaction which necessitates isolation of the intermediate Product.            3) Reacting 2-chlorobenzoyl chloride (e.g. WO 2009/010163, method D) with a thiocyanate salt and subsequently treating the crude 2-chlorobenzoylthicoyanate with the corresponding secondary amine (EP 2 029 583). In this method, the yield of the final product is in the range of below 1% which is unsatisfactory and unsuitable for industrial application.
In view of these drawbacks, it is highly desirable to provide a process for preparing 2-amino-substituted 1,3-benzothiazine-4-ones, especially 2-(homo)piperazine-1,3-benzothiazine-4-one derivatives which is superior to the prior art methods and which is suitable for manufacture in an industrial scale.
It has surprisingly been found that 2-(homo)piperazine 1,3-benzothiazine-4-one hydrochlorides of general formula (Ia) can be obtained in a high yield by (1) reaction of 2-chloro-3-nitro-5-(trifluoromethyl)benzoyl chloride of general formula (II) with a thiocyanate salt M-SCN, (2) followed by reaction with a 2-substituted piperazine or homopiperazine, and (3) acidification with hydrochloric acid.

By way of this process, the hydrochlorides of general formula (Ia) are obtained in high yields (58%-78%) and high purity in a one pot-reaction. This finding was very surprising because it was known from the prior art that the reaction of piperidine derivatives with an isothiocyanate results in very low yields of below 1% (see EP 2 029 583).